Advances in the treatment of metastatic prostate cancer

Gebrael, Georges; Fortuna, Gliceida M Galarza; Sayegh, Nicolas; Swami, Umang; Agarwal, Neeraj

doi:10.1016/j.trecan.2023.06.009

Cited by 11 publications

(18 citation statements)

References 52 publications

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“…Recently, novel combinations such as poly‐ADP ribose polymerase inhibitors added to ARPI have been approved in first‐line treatment for patients with mCRPC harboring selective homologous recombination repair mutations 1 . In those clinical trials, around 5% of patients had progressed on prior ARPI and around 20% on prior docetaxel 12 .…”

Section: Discussionmentioning

confidence: 99%

“…Androgen deprivation therapy (ADT) intensification (ADTi) with an androgen receptor pathway inhibitor (ARPI) or docetaxel, or both, has significantly improved survival outcomes in patients with metastatic hormone‐sensitive prostate cancer (mHSPC) 1 reaching 47.6 months for progression‐free survival (PFS) and 81.1 months for overall survival (OS) in one of the registration trials 2 . However, the early use of therapeutic agents hitherto in hormone‐sensitive settings may impact the disease characteristics and survival outcomes of metastatic castration‐resistant prostate cancer (mCRPC).…”

Section: Introductionmentioning

confidence: 99%

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Natural course of metastatic castration‐resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone‐sensitive setting

Gebrael,

Hage Chehade,

Sayegh

et al. 2024

The Prostate

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BackgroundAndrogen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone‐sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration‐resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting.MethodsIn this institutional review board‐approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first‐line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression‐free survival (PFS) was defined from the start of first‐line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first‐line therapy for mCRPC to death or censored at the last follow‐up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders.ResultsPatients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate‐specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07–2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06–2.21, p = 0.022) compared to patients in the nonintensified ADT group.ConclusionPatients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first‐line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life‐prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Natural course of metastatic castration‐resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone‐sensitive setting

Gebrael,

Hage Chehade,

Sayegh

et al. 2024

The Prostate

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“…2 The most well-known prostate cancer predisposition gene is BRCA2, with deleterious germline BRCA2 variants strongly associated with poor prognosis across the spectrum of disease, and also conferring sensitivity to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in the metastatic castrationresistant setting. 3,4 The genes TP53, ATM, MSH2, and several other genes directly or indirectly linked with DNA damage repair processes are also associated with clinically-aggressive prostate cancer and/or response to PARP inhibitors or immune checkpoint inhibitors. 2,5 The low prevalence of high-penetrance germline alterations has made it historically difficult to understand the true effect size for risk of clinically-aggressive prostate cancer.…”

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confidence: 99%

“…Some of the rare or newly implicated genes for aggressive prostate cancer (eg, RAD51D, MRE11A, NBN) have plausible links to DNA homologous recombination repair (HRR). An HRR deficiency predicts the response to PARP inhibition, 4 but it is only induced by complete loss of an integral HRR gene. Most DNA damage repair genes, including HRR pathway members, do not result in functional deficiency when only 1 allele is mutated or deleted.…”

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confidence: 99%

“…This paradigm persisted until the evidence-based replacement of axillary dissection with the far less morbid approach of sentinel node biopsy for pathological staging of the clinically negative axilla. 2,3 The use of axillary dissection was further eroded by the landmark American College of Surgeons Oncology Group Z0011 trial, 4 which demonstrated that diseased lymph nodes could be left intact without impairing breast cancer outcomes, given effective systemic therapy. Most recently, the 10-year results of the AMAROS trial demonstrated equivalent outcomes in women who received axillary dissection or axillary radiotherapy for limited nodal disease in the axilla, with reduced rates of arm lymphedema.…”

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Rare Genetic Drivers of Lethal Prostate Cancer

Wyatt

2023

JAMA Oncol

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Genetic testing is a recently adopted standard of care for male patients with metastatic or high-risk localized prostate cancer. 1 Rare deleterious germline alterations in a small number of cancer-associated genes are relevant for clinical management and/or selection of systemic therapy. 2 The most well-known prostate cancer predisposition gene is BRCA2, with deleterious germline BRCA2 variants strongly associated with poor prognosis across the

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Bone Pain and Survival Among Patients With Metastatic, Hormone-Sensitive Prostate Cancer

Gebrael,

Jo,

Swami

et al. 2024

JAMA Netw Open

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ImportanceThe presence of bone pain is significantly associated with worse overall survival (OS) in patients with castration-resistant prostate cancer. However, there are few data regarding bone pain and survival outcomes in the context of metastatic, hormone-sensitive prostate cancer (MHSPC).ObjectiveTo compare survival outcomes among patients with MHSPC by presence or absence of baseline bone pain at diagnosis.Design, Setting, and ParticipantsThis post hoc secondary analysis, conducted from September 1 to December 31, 2023, used patient-level data from SWOG-1216, a phase 3, prospective randomized clinical trial that enrolled patients with newly diagnosed MHSPC from 248 academic and community centers across the US from March 1, 2013, to July 15, 2017. All patients in the intention-to-treat population who had available bone pain status were eligible and included in this secondary analysis.InterventionsIn the SWOG-1216 trial, patients were randomized (1:1) to receive either androgen deprivation therapy (ADT) with orteronel, 300 mg orally twice daily (experimental group), or ADT with bicalutamide, 50 mg orally daily (control group), until disease progression, unacceptable toxic effects, or patient withdrawal.Main Outcomes and MeasuresOverall survival was the primary end point; progression-free survival (PFS) and prostate-specific antigen (PSA) response were secondary end points. Cox proportional hazards regression models were used for both univariable and multivariable analyses adjusting for age, treatment type, Gleason score, disease volume, Zubrod performance status, and PSA level.ResultsOf the 1279 male study participants, 301 (23.5%) had baseline bone pain at MHSPC diagnosis and 896 (70.1%) did not. Bone pain status was unavailable in 82 patients (6.4%). The median age of the 1197 patients eligible and included in this secondary analysis was 67.6 years (IQR, 61.8-73.6 years). Compared with patients who did not experience bone pain, those with baseline bone pain were younger (median age, 66.0 [IQR, 60.1-73.4] years vs 68.2 [IQR, 62.4-73.7] years; P = .02) and had a higher incidence of high-volume disease (212 [70.4%] vs 373 [41.6%]; P &lt; .001). After adjustment, bone pain was associated with shorter PFS and OS. At a median follow-up of 4.0 years (IQR, 2.5-5.4 years), patients with bone pain had median PFS of 1.3 years (95% CI, 1.1-1.7 years) vs 3.7 years (95% CI, 3.3-4.2 years) in patients without initial bone pain (adjusted hazard ratio [AHR], 1.46; 95% CI, 1.22-1.74; P &lt; .001) and OS of 3.9 years (95% CI, 3.3-4.8 years) vs not reached (NR) (95% CI, 6.6 years to NR) in patients without initial bone pain (AHR, 1.66; 95% CI, 1.34-2.05; P &lt; .001).Conclusions and RelevanceIn this post hoc secondary analysis of the SWOG-1216 randomized clinical trial, patients with baseline bone pain at MHSPC diagnosis had worse survival outcomes than those without bone pain. These data suggest prioritizing these patients for enrollment in clinical trials, may aid patient counseling, and indicate that the inclusion of bone pain in prognostic models of MHSPC may be warranted.Trial RegistrationClinicalTrials.gov Identifier: NCT01809691

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Advances in the treatment of metastatic prostate cancer

Cited by 11 publications

References 52 publications

Natural course of metastatic castration‐resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone‐sensitive setting

Natural course of metastatic castration‐resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone‐sensitive setting

Rare Genetic Drivers of Lethal Prostate Cancer

Bone Pain and Survival Among Patients With Metastatic, Hormone-Sensitive Prostate Cancer

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